Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.2.1.20 (alpha-glucosidase)
 4,237 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glycogen storage disease type II (GSDII) is a recessively inherited disorder caused by defects in lysosomal acid alpha-glucosidase. In an attempt to reproduce the range of clinical manifestations of the human illness we have created null alleles at the acid alpha-glucosidase locus (GAA) with several gene targeting strategies. In each knockout strain, enzyme activity was completely abolished and glycogen accumulated at indistinguishable rates. The phenotypes, however, differed strikingly. Acid alpha-glucosidase deficiency on a 129xC57BL/6 background resulted in a severe phenotype with progressive cardiomyopathy and profound muscle wasting similar to that in patients with glycogen storage disease type II. On a 129/C57BL/6xFVB background, homozygous mutants developed a milder phenotype with a later age of onset. Females were more affected than males irrespective of genetic background. As in humans with glycogen storage disease type II, therefore, other genetic loci affect the phenotypic expression of a single gene mutation.
 ...
PMID:Modulation of disease severity in mice with targeted disruption of the acid alpha-glucosidase gene. 1083 56

The importance of proper lysosomal activity in cell and tissue homeostasis is underlined by "experiments of nature", i.e. genetic defects in one of the at least 40 lysosomal enzymes/proteins present in the human cell. The complete lack of 1-4 alpha-glucosidase (glycogen storage disease type II (GSD II) or Pompe disease) is life-threatening. Patients suffering from GSD II commonly die before the age of 2 years because of cardiorespiratory insufficiency. Striated muscle cells appear to be particularly vulnerable in GSD II. The high cytoplasmic glycogen content in muscle cells most likely gives rise to a high rate of glycogen engulfment by the lysosomes. The polysaccharides become subsequently trapped in these organelles when 1-4 alpha-glucosidase activity is absent. During the course of the disease, muscle wasting occurs. It is hypothesised that the gradual loss of muscle mass is caused by a combination of disuse atrophy and lipofuscine-mediated apoptosis of myocytes. Moreover, we hypothesise that in the remaining skeletal muscle cells, longitudinal transmission of force is hampered by swollen lysosomes, clustering of non-contractile material and focal regions with degraded contractile proteins, which results in muscle weakness.
 ...
PMID:Lysosomal dysfunction in muscle with special reference to glycogen storage disease type II. 1263 5

A hallmark of glycogen storage disease type II, caused by defective alpha-glucosidase (AGLU) activity, is a progressive decline in muscle performance. The objective of this study was to determine the relative contribution to this decline in muscle performance of (1) decline in muscle mass; (2) decline in muscle protein content per unit mass; and (3) accumulation of glycogen. To this end, isometric torque and power in AGLU(-/-) mice at 7, 13, and 20 months were assessed in situ. Power (approximately 24 mW) and torque (approximately 2.45 Nmm) did not change with age in control animals, but declined significantly in AGLU(-/-) mice, in the three age groups. No decline in protein content per unit muscle mass was observed. Muscle atrophy explained one third of the decline in muscle performance; the remaining part was attributed to a decrease in muscle quality--a decrease in mechanical performance per unit muscle mass. Mechanical effects of glycogen inclusions could not fully explain this decrease. Additional factors must therefore play a role.
 ...
PMID:Age-related decline in muscle strength and power output in acid 1-4 alpha-glucosidase knockout mice. 1567 28